Acute Myeloid Leukemia (AML) patients respond favorably to induction chemotherapy treatment, however due to a high rate of minimal residual disease, a significant majority patients fatally relapse. The interactions between AML cells and the bone marrow microenvironment are critical for AML disease progression and relapse. The bone marrow niche can provide a protective environment for leukemic stem cells (LSCs) and is often the primary site for minimal residual disease after chemotherapy. Therefore, in order to improve long- term patient outcomes it is critical to expand our focus to the development of therapies that are specifically directed towards the AML cell population that is residing within the bone marrow. The objective of our proposed work is to elucidate how the membrane-scaffold protein, CD82, modulates AML response to chemotherapy and promotes minimal residual disease. We hypothesize that CD82 expression, which is increased in the LSC population, in AML cells promotes chemoresistance and AML/bone marrow interactions contributing to minimal residual disease. In Specific Aim 1, we will identify the impact of CD82 expression on AML chemosensitivity and survival signaling using a combination of engineered human cell lines and primary patient samples. For Specific Aim 2, we will evaluate how CD82 expression contributes to the quiescent state of AML cells in the bone marrow, specific niche localization within the bone and the impact on minimal residual disease. This contribution is significant because! we expect to identify novel mechanisms that can be targeted to disrupt AML interactions with the bone marrow microenvironment. Moreover, this proposal is innovative because it will apply a combinatorial experimental approach to investigate the chemoresistant population of AML. By utilizing genetically engineered cell lines, mouse models, and primary patient samples, we will integrate biochemical, molecular and morphological information to acquire a multi-scale understanding of how CD82 modulates AML/niche interactions that promote chemoresistance, quiescence and minimal residual disease.